1. Field of the Invention
The present invention relates (a) to substituted piperidine compounds and more particularly to 4,4-diarylpiperidines which are or are not substituted in the 1-position of the piperidine nucleus and/or in at least one of the aryl rings, (b) to an advantageous process for making such compounds, (c) to pharmaceutical compositions containing same, and (d) to methods of using such compositions in therapy for their central nervous system stimulating effect.
2. Description of the Prior Art
1-Methyl-4,4-diphenylpiperidine and 1-(secondary butyl)-4,4-diphenylpiperidine are mentioned in Brit. J. Pharmacol., Vol. 10, pages 270 to 278 (1955), by Marshall, the disclosure thereof is incorporated herein (in its entirety) by reference. Both compounds are tested by Marshall for their antihistaminic activity using the structure of Schild [Brit. J. Pharmacol. (1947), Vol. 2, pages 189 to 206]. From inspection of Table II (pages 272 and 273) and of FIG. 3 (page 275) of the Marshall citation, it is evident to the pharmacologist skilled in the art that both compounds, 1-methyl-4,4-diphenylpiperidine and 1-(secondary butyl)-4,4-diphenylpiperidine are devoid of any therapeutically utilizable antihistaminic activity.
N. Sperber et al. describe [Journ. Am. Chem. Soc., Vol. 75, pages 1122 to 1125 (1953)] processes for preparing 1-methyl-4,4-diphenylpiperidine. According to one process diphenyl methane is reacted with 2-dimethylaminoethyl chloride to produce 3,3-diphenyl-N,N,N',N'-tetramethyl-1,5-pentanediamine. On ring closure, 1-methyl-4,4-diphenylpiperidine is obtained in a low yield.
According to a second process disclosed by Sperber (loc. cit.) diphenylmethane is reacted with 2-bromoethyl ethyl ether to yield 3,3-diphenyl-1-ethoxypropane. Alkylation of 3,3-diphenyl-1-ethoxypropane with 2-dimethylaminoethyl chloride yielded 5-ethoxy-3,3-diphenyl-N,N-dimethylamylamine; cleavage of the ethoxy group gave 5-hydroxy-3,3-diphenyl-N,N-dimethylamylamine hydrobromide, which was reacted with thionyl chloride to give 4,4-diphenyl-1,1-dimethylpiperidinium chloride, from which sublimation in vacuo yielded 1-methyl-4,4-diphenylpiperidine. This synthesis includes 5 reaction steps and provides an overall maximum yield of about 23 percent of theory. The availability of this synthesis for the preparation of homologues of 1-methyl-4,4-diphenylpiperidine, e.g. of 1-ethyl-4,4-diphenylpiperidine or 1-isopropyl-4,4-diphenylpiperidine has to be regarded as doubtful.
Sperber refers to L. O. Randall and G. Lehmann, J. Pharmacol. Exp. Therap., Vol 93, pages 314 to 328 (1948), who evaluated 1-methyl-4,4-diphenylpiperidine along with several other series of compounds, and found it to be devoid of analgesic activity [See Sperber (loc. cit.), footnote 5 on page 1122].
With regard to the process for the preparation of 4,4-diarylpiperidines hereinafter described and claimed and its status as a non-analogous process in view of the background of the prior art, the disclosure of the article of N. G. Sidorova et al., J. Gen. Chem. USSR, Vol. 7, pages 1830 to 1833 (1957), is incorporated herein by reference.
In U.S. Pat. No. 3,468,893 Mizzoni discloses the preparation of 1-substituted diphenylazacycloalkenes, which compounds are supposed to be useful as hypotensive agents. The general formula given by Mizzoni encompasses an immense number of substituted azacycloalkenes of which the alkyleneimino ring may represent piperidino, pyrrolidino, 1,5-, 1,6- or 2,5-hexyleneimino, 1,5-, 1,6-, 1,7- or 2,6-heptyleneimino or 1,8-, 3,6- or 3,7-octyleneimino. In Example 13 of the patent, inter alia, the compounds 1-(2-hydroxy- or chloro-ethyl)-4,4-diphenylpiperidine are mentioned but apparently no 4,4-diphenylpiperidine was actually prepared. In fact, the synthetic methods discussed in the patent for the preparation of the various 1-substituted diphenylazacycloalkenes either could not be adapted for the preparation of 4,4-diphenylpiperidines, or starting materials, such as 2,2-diphenylglutaric acid mononitrile ethyl ester, are unknown and unavailable.